This invention relates to stabilizers for radiopharmaceutical compositions. More particularly, stabilizers such as gentisic acid and its derivatives, alone or in combination with other stabilizers, are used to inhibit autoradiolysis of radiolabeled peptides and proteins.
The number of therapeutic and diagnostic uses of radiolabeled compositions is continually growing. Such uses generally involve the introduction of a suitable radiolabeled composition into a biological subject. Detection and imaging of radioactive emissions may be used to diagnose and locate the presence of aberrations, pathological conditions, and the like. In some cases, the radiolabeled composition may be designed to locate in or to seek out specific tissues or biological receptors for the purpose of delivering therapeutic radioactive emissions.
In general, a radiolabeled composition comprises a radionuclide, a carrier agent designed to target the specific organ of interest, various auxiliary agents which affix the radionuclide to the carrier, a delivery vehicle, such as water, suitable for injection into or aspiration by the patient, physiologic buffers and salts, and the like.
Some radiopharmaceutical preparations are known to require stabilizers. For example, technetium-99m and rhenium-186 compositions are unstable in oxygen and require stabilizers, such as antioxidants or reducing agents, to maintain the technetium or rhenium in a usable oxidation state. Typical reducing agents used in technetium-99m and rhenium-186 compositions include stannous, ferrous, and chromous salts. Sometimes other additives, such as ascorbic acid, d-ascorbic acid, gentisic acid, reductic acid, erythorbic acid, p-aminobenzoic acid, 4-hydroxybenzoic acid, nicotinic acid, nicotinamide, and 2,5-dihyroxy-1,4-benzenedisulfonic acid, are included to inhibit the oxidation of the radionuclide or the reducing agent.
Other radionuclides, such as .sup.111 In, .sup.90 Y, and .sup.67 Ga exist in a stable oxidation state, and therefore, do not require stabilizers to maintain their useful oxidation state.
Over the years, there has been growing interest in preparing radiolabeled proteins such as hormones, macroaggregated albumin ("MAA"), human serum albumin ("HSA"), monoclonal antibodies, or monoclonal antibody fragments for the purpose of diagnosing and treating diseases, such as inflammation, deep vein thrombosis, or cancer. In some cases, autoradiolysis of the labeled protein has been observed. To inhibit or prevent autoradiolysis, experts have suggested adding HSA to the composition (e.g., R.A.J. Kishore, et al., "Autoradiolysis of Iodinated Monoclonal Antibody Preparations," Int J. Radiat. Appl. Instrum., Part B, Vol. 13, No. 4, pp. 457-459 (1986)) or keeping the radiopharmaceutical composition frozen between preparation and administration (e.g., R. L. Wahl, et al., "Inhibition of Autoradiolysis of Radiolabeled Monoclonal Antibodies by Cryopreservation," J Nuc. Med., Vol. 31, No. 1, pp. 84-89 (1990)). These techniques for preventing autoradiolysis are often not effective or practical when used with many radiolabeled peptides and proteins.
Recently, a number of exciting new peptides for diagnostic and therapeutic applications have been isolated and synthetically developed. One such peptide is an octapeptide somatostatin analog known as octreotide and described in U.S. Pat. No. 4,395,403. Octreotide has a very high binding affinity to somatostatin receptors in a variety of human tumors. By linking octreotide to a suitable chelating agent capable of forming a complex with radionuclides, it has been possible to create radiolabeled octreotide which effectively images tumors having somatostatin receptors. Somatostatin analogs containing chelating groups are described in UK Patent Publication No. 2,225,579.
Despite the potential usefulness of radiolabeled peptides, it has been found that they are very susceptible to autoradiolysis. As used herein, the term autoradiolysis includes chemical decomposition of the peptide by the action of radiation emitting from the radioisotope coupled to the peptide. Some believe autoradiolysis may be caused by the formation of free radicals, such as hydroxyl radicals, in the water or delivery vehicle by the radiation emitted from the radioisotope.
From the foregoing, it will be appreciated that what is needed in the art are stable radiolabeled peptide and protein compositions. Thus, it would be a significant advancement in the art to provide stabilizing agents which substantially inhibit autoradiolysis of radiolabeled peptides and proteins.
Such compositions for substantially inhibiting peptide and protein autoradiolysis are disclosed and claimed herein.